Evidence for homeopathic principles in the basic ... - Paolo Bellavite

Evidence for homeopathic principles in the basic sciences Paolo Bellavite Department of Medicine, University of Verona (I) Email: [email protected]

Cape Town 5 Sept 2018

© P. Bellavite, Università di Verona

Evidence for homeopathic principles in the basic sciences 1. 2. 3. 4.

Introduction Similia Microdose and «potency» Key points

Note: Tables and figures of this presentation are available at: http://www.paolobellavite.it/news.html Cape Town 5 Sept 2018


“Art” and “Science” in Medicine

As every field of medicine, homeopathy is characterized by aspects which belong to the “art” of healing and by aspects which are belonging to scientific medicine. The two “wings” are not in contrast and should be taken into account for a whole evaluation of the medical system. A rigorous scientific research has been carried out in the last 30 years and now we have over 6000 scientific papers in top literature (Pubmed)



SCIENTIFIC INVESTIGATION OF THE HOMEOPATHIC PRINCIPLES HOW DOES IT WORK?

•In vivo (animal models) •In vitro (cellular systems) •Physico-chemistry (“water memory”) •Dynamic systems theory

Basic sciences

•Drug composition •Drug targets (cells/organs/systems)

SIMILIA MICRODOSE AND PRINCIPLE “POTENCY”

TOTALITY OF CURE DOES IT WORK? •Adverse effects? •Is it cost-effective? •COULD IT WORK BETTER? Cape Town 5 Sept 2018

Clinical research

• • • •

Provings Observational studies Prognostic factors research Randomized trials © P. Bellavite, Università di Verona

Laboratory models and homeopathy •

Homeopathy is directed toward the complexity of the whole organism, through mechanisms that are not yet clarified.

•

Such action may also appear at the cell level

•

Given the holographic fractal nature of all complex systems, the fundamental rules of biological responses/pathologies can be unraveled at any level of nature, from the complex organism to the single cells (eg. complete genome in each cell)

•

Our working hypothesis (and dr. Benveniste was a pioneer!) is that the biological investigation at the cell level, makes it possible to look at homeopathy in a new and fully rational light

Complex systems

Objects of research:

 Drug targets (receptors, enzymes, gene expression)  Specific mechanisms of action Cape Town 5 Sept 2018


Basic research in homeopathy TYPICAL CELLULAR MODELS https://www.ncbi.nlm.nih.gov/pubmed/26678723

• Lymphocytes (Colas, Bildet, Bastide, Wagner, Chirila, Fimiani, Seligmann, Toliopulos, Coelho Moreira, Guimarães, Burbano)

• Basophils (Poitevin, Sainte Laudy, Belon, Davenas, Ovelgonne, Hirst, Mannaioni, Ennis, Bellavite, Baumgartner)

• Granulocytes, macrophages (Poitevin, Fletcher, Bellavite) • Cell lines: Fibroblasts (Boiron, Mansvelt, Fougeray, Valentiner, Saini) Renal cells (Delbancut), Hepatoma (van Wijk, Wiegant), Prostate epitelial (Bigagli) . Neurocytes (Jonas, Bellavite), Macrophages (Bonamin, De Oliveira, Olioso, Marzotto, Siqueira)

• Vegetable cells (Guillemain, Bornoroni, Betti, Sukul, Baumgartner) • Cancer cells (Jonas, Frenkel, Khuda-Buckhsh, Arora, Saha, Das)



Results of models of basic research submitted to replication (total = 98 studies until 2015)

Opposite result

No effect

Positive replication

External replications Multicentre Internal replications

Initial studies-20

0

20

40

https://www.ncbi.nlm.nih.gov/pubmed/26678723

Replications of fundamental research models in ultra high dilutions 1994 and 2015 e update on a bibliometric study. Peter Christian Endler, Paolo Bellavite, Leoni Bonamin, Tim Jager and Sintia Mazon Homeopathy (2015) 104, 234e245



Some (not all!) players

Jacques Benveniste – F (Basic research)

Madeleine Bastide - F (Immunology)

Vittorio Elia - I (Chemistry)

Lucietta Betti - I (Botanical research)

Carla Holandino - BR (Pharmacology)

Philippe Belon - F (Basic research)

Louis Rey - F (Thermoluminescence)

Christian Endler - A Leoni Bonamin – BR (Basic research) (Basic research)

A. Khuda Bukhsh - Ind (Biochemistry)


Nirmal Sukul - Ind (Basic science)

Thank you Peter! © P. Bellavite, Università di Verona





TESTING HOMEOPATHY MAIN HYPOTHESIS IS A SCIENTIFIC ISSUE

“The majority of substances have more than one action; the first is a direct action, which gradually changes into the second, which I call its indirect secondary action. The second is generally the opposite of the first” C.F.S. Hahnemann, 1796 TRUE

C.F.S. Hahnemann

FALSE

SCIENTIFIC RESEARCH + Cape Town 5 Sept 2018


Janus Ancient symbol of similitude

ENTRY

EXIT

PAST

FUTURE

BEGINNING

ENDING

NEGATIVE

POSITIVE Axis (Roman coin)



SCIENTIFIC REEVALUATION OF THE HOMEOPATHIC “SIMILE”

GENERAL HYPOTHESIS:

The “therapeutic similarity” in drug action may be fundamentally based on the widespread phenomenon of inversion of biological effects dependent on the following factors:

1. the dose of the drug, and/or 2. the pathophysiological state of the target

Main references in: Bellavite et al .: ECAM Journal 2007 (available online https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876612/pdf/nel117.pdf) Cape Town 5 Sept 2018


Experimental studies on APIS M. (1975-2015) Madeleine Bastide (1935-2007) 1975 Homeopahtic dilutions (7C-9C) of bee venom (Apis mellifica and Apium

1988 1993

2004 2014

virus, have a protective and curative effect on X-ray induced erythema in albino guinea pig (Bastide1975, Bildet1989, 1990) High dilutions of Apis mellifica inhibit basophil degranulation (histamine release) (Poitevin et al., 1988) Our group studied the effects of homeopathic preparations of Apis mellifica (and Histamin) on rat paw edema induced by the injection of inflammatory doses of histamine. High dilutions of up to 30D had a small but significant inhibitory effect on the development of edema (Conforti et al.,1993). We described a small inhibiting effect of Apis mellifica (4 D, oral drops) in the carrageenan-induced edema in rats . Bigagli and coworkers (2014) showed with microarray techniques that Apis mellifica TM modifies expression of hundreds of genes in human prostate epithelial cells; dynamized dilutions (3C, 5C and 7C) still exert significant effects on genes involved in inflammation and oxidative stress



FIRST «homeopathic» paper in top Journal

Bernard Poitevin



EXAMPLES OF INVERSE EFFECTS IN LABORATORY SYSTEMS (“conventional” dilutions)

System

Agent

First effect

Inverse effect

Ref.

Yeast

Heavy Metals

Block growth

Low doses increase growth

Schulz 1988 Martius 1923 Stebbing 1982

Fibroblasts Wheat

Arsenite Cadmium

Cell toxicity

Low doses protect from toxicity or stimulate DNA synthesis

vanWijk 1995 vanWijk 1997 V.Zglinicki 1992 Betti 1997-2000

Neurons

Naloxone

Antagonizes morphine

Low doses enhance the effect of morphine

Crain 1995

Neurons

b-amyloid

Toxic for mature cells

Promotes growth of young cells

Yankner 1990 See also Puzzo 2018

Epithelial cells Tumor cells

Oxidants

Short-term/high doses decrease viability

Long-term/low doses increase viability

Da Silva 1996 Jenkins 1995

Macrophages

Interfererons Endotoxins

Activation of resting cells

Inhibition of pre-activated cells

Adams 1992

Platelets

Diclofenac

Inhibit functions

Stimulate platelet adhesion

Andrioli-Bellavite 1997

Leukocytes

Bacterial peptides

Stimulate adherence

Low doses inhibit adherence

Bellavite 19931997

http://www.paolobellavite.it/files/246_2011SeminarioRomaRey_58wwpoeh.pdf Cape Town 5 Sept 2018


Inverse effects of Amyloid-b according to the dose https://www.ncbi.nlm.nih.gov/pubmed/19118188



THE “SIMILE” IN THE LIFE: EXAMPLES OF “OPPOSITE” or “INVERSE” EFFECTS (Homeopathic dilutions) Ref: https://www.ncbi.nlm.nih.gov/pubmed/17549232

System

Agent

“Conventional” effect

“Homeopathic” effect

Ref.

Rat, Guinea pig

Histamine Pro-inflammatory Histamine (30x), Lung histamine Bastide 1975,Poitevin Lung Histamine agent (18c) and Apis mellifica (7c/10c) 1988, Bildet 1990 Apis mell. reduce inflammation symptoms Conforti 1993

Rat, Mouse

Arsenic

Whole body and liver toxicity

Ars. high dilutions (7c-30c) protect from intoxication

Lapp 1955; Wurmser 1955; Cazin1987-1991; Banerjee,P, Khuda-Bukhsh 1998-2000

Rat

Nux vomica

Neurohinibition (strychnine)

Reduces alchool-indced sleeping time

Sukul et al., 1999

Rat

Acetylsalycilic acid

Antithrombotic

Acetylsalycilic acid (5c-15c) has Beulogne-Malfatti,Doutremepuich , Eizayag et al. pro-thrombotic effects

Phosphorus

Hepatotoxicity

Rat

1998-2012

Phosphorus high dilutions (30x) Bildet 1984, Guillemain protects from toxic hepatitis 1987 Palmerini 1993

Tadpoles Thyroxine

Increases the rate Thyroxine high dilutions (up to of metamorposis 30x) inhibit metamorphosis

Endler 1990-2014, Lingg 2008, Weber 2008, Guedes 2011, Harrer 2013

Rat, Mouse

Gelsemium s.

Toxic and convulsivant

Anxiolytic effect (2c-30c) of Gelsemium s.

Magnani 2010, Venard 2011, Bellavite 2012

Wheat

Arsenic

Cell toxicity

Ars. high dilutions (45x) stimulate vitality

Betti et al. 1997-2014



PARADOXICAL EFFECTS OF ASPIRIN (1990-2013) and Aguejouf,O.; BelougneMalfatti,E.; Doutremepuich,F.; Belon,P.; Desplat, V;

Dr Christian Doutremepuich

Dr Francisco Eizayaga

Ref: https://www.ncbi.nlm.nih.gov/pubmed/22292117

High dose (500 mg) Low dose (50-100 mg)

«Rebound» effects and High dilutions (9-15-30CH)

Anti-thrombotic (Pro-haemorragic) Cape Town 5 Sept 2018

Pro-thrombotic Adverse «Homeopathic» effect use?

(Anti-haemorragic) © P. Bellavite, Università di Verona

SCIENTIFIC REEVALUATION OF THE HOMEOPATHIC “SIMILE”

IMPORTANT NOTE The inversion of biological effects dependent on the dose of the drug (“hormesis”) has been confirmed in a number of well-designed model systems, but is NOT a general rule for homeopathy. In fact, high homeopathic dilutions (extremely low doses, or «no doses») often act in the same direction of low dilutions (ponderal doses)



EFFECTS OF HISTAMINE AND ON HUMAN BASOPHILS Chirumbolo , Bellavite et al., Inflammation Research 2009

HISTAMINE

Histamine low dilution (2C, ponderal)


WATER CONTROL

(positive control)


MODEL OF THE HISTAMINE ACTION ON BASOPHILS AND MAST CELLS (Belon, Mannaioni et al.)



Action of homeodrugs at receptor level LOW DILUTIONS (e.g. 2CH-5CH)

HIGH DILUTIONS (e.g. 9CH-30CH) CIMETIDINE

H

H

Inhibition of Basophils

Histamine Low dilution PROPRANOLOL

A

Histamine High dilution PROPRANOLOL

Inhibition of Basophils

A

Adrenaline Low dilution

Adrenaline High dilution

Anxiolytic-like effect Gelsemium Gelsemine Low dilution

Gels


STRYCHNINE

Gels

Gelsemium Gelsemine High dilution






TESTING HOMEOPATHY MAIN HYPOTHESIS IS A SCIENTIFIC ISSUE!

“A medicine whose selection has been accurately homoeopathic must be all the more salutary the more its dose is reduced to the degree of minuteness appropriate for a gentle remedial effect...”

C.F.S. Hahnemann

C.F.S. Hahnemann, 1810 Organon, par. 277 TRUE

FALSE

SCIENTIFIC RESEARCH Cape Town 5 Sept 2018


The famous and controversial paper of «Water memory» Davenas, E., Benveniste, J., et al. Nature 333: 816-818, 1988.

Jacques Benveniste (1935 – 2004)



EXAMPLES OF HIGH DILUTION EFFECTS “IN VITRO” System

Agent

Dilution

Human basophils

Apis, Histamine

12C-16C 10-24 10-32

Inhibition of activation markers

Human basophils

Adrenaline

Inhibition of activation markers

Cicken embrio

Bursin

12C-16C 10-24 10-32 15 C (10-27g)

Human neutrophils Wheat germination Rat neurons

Phosphorus

12 D to 30 D

Arsenic Silver nitrate Glutamate

26 D (10-45 )

Neurocytes Bacteria

Cycloheximide Arsenicum

10-27 30C

Neurocytes

Gelsemium s.

2-30 C

Colon cancer cells Macrophages

Ruta grav.

MT-30C

Arnica montana

2-15C

Epitelial cells

Apis mellifera

3-30C


10-18 10-30

Ref.

Effect

Poitevin 1988, Belon 1999-2009 (and Verona Group) Mannaioni et al. 2010

Immunomodulatory and endocrine activity Inhibition of superoxide production Protect from toxicity Enhances growth Protection from glutamate toxicity Increases viability Protects from toxicity Prevalent gene downregulation Decrease viability, apoptotic gene expression Modulates inflammatory genes Modulates hundreds of genes

Bastide, YoubicierSimo 1993-97 Chirumbolo and Bellavite 1993 Betti 1997/2015 Pongratz 1998 Jonas et al., 2001 Marotta 2002 Das et al 2011, De et al 2012 Marzotto 2014, Olioso 2014 Arora and Tandon 2015 Olioso 2016, Marzotto 2016 Bigagli 2016


Gelsemium sempervirens as a model of laboratory investigation of homeopathy (Verona lab 2008-2018)

Gelsemine

Possible analogy with (SOME) human symptoms Repertorial Materia Medica: Result of search by index in all repertories: [root:WALK] AND [root:AMEL] MIND - ANXIETY - walking - air, in open – amel. 7 MIND - ANXIETY - walking – amel. 8  MIND - WALKING - air; in the open – amel. 20 GENERALS - WALKING - air; in open – amel. 135 GENERALS - WALKING - rapidly – amel. 19 GENERALS - WALKING - slowly – amel. 15 Materia Medica (Boenninghausen, Murphy): MIND: FEELING AS IN DANGER OF FALLING MIND: DREAD/DESIRE OF BEING ALONE MIND: IMPATIENT AND IRRITABLE MIND: NERVOUS DREAD OF APPEARING IN PUBLIC



C. TIME SPENT IN LIT AREA (anxiolytic-like effect)

EFFECT (% of control placebo)

En field

A. GENERAL MOVEMENT (total distance travelled, movement and possibly sedation)


Light Dark


Open field


Anxiolytic-like effect on mice behaviour (Verona lab 2008-2012) B. TIME SPENT IN CENTRAL AREA (index of exploration attitude)

NO TOXIC EFFECTS

D. LIGHT-DARK transitions (anxiolytic-like effect and movement)

*